failure analysis for update

Michael N. Helmus, Ph.D., [email protected]

Failure Analysis: Reevaluating Functional Requirements of Medical Devices

Failure Analysis: Reevaluating Functional Requirements of Medical Devices Invited Speaker, “Failure Analysis: Reevaluating Functional

Requirements of Medical Devices”, Opportunities for Next Generation Medical Devices,

Aug 5-7, 2008, Cleveland Clinic and ASM International.

New devices require diverse skills while utilizing biocompatible, biomechanical, bioactive, & nanoenabled mat'ls. http://tpx.sagepub.com/content/36/1/70.full.pdf+html These disruptive technologies will drive personalized medicine. http://www.iscpubs.com/Media/PublishingTitles/a0306hel.pdf Understanding the design process & failure analysis will facilitate & accelerate medical device development (M. N. Helmus, "Biomaterials in the design and reliability of medical devices", Kluwer & Landes Bioscience, 2003).

Let me help you with your development efforts (contact me for a special one day rate during Dec. 2010 ).

cell (508) 269 6021 fax (508) 519 [email protected]

Michael N. Helmus, Ph.D., Consultant

Medical Devices, Biomaterials, Drug Delivery, and Nanotechnology

(508) 767 0585


Agenda

• Introduction: Failure with focus on Materials and Design

• Biologic Reactions and Biocompatibility

• Biologic Issues

• Explant analysis paradigm

• Failures

• Personal anecdotes

• Commercial products

•Emerging Technologies and New Failure Modes


The Wall Street JournalThe Wall Street JournalFri. Aug 22, 2003Fri. Aug 22, 2003

Need for joint replacements at younger ages!



M. N. Helmus, ed., "Biomaterials in the design and reliability of medical devices", Kluwer Academic/Plenum Publishers and Landes Bioscience, NY, NY and Georgetown, TX, 2003.

BiocompatibilityBiocompatibility


FAILURE ANALYSIS AND THE MEDICAL DEVICE VALUE CHAIN

Ben

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Technology Medicine

Develop IP Strategy: Composition of Matter ApplicationsFile IP

Redesign Redesign Post Market SurveillanceRedesign


Commercializing Technology

Medical Centers

Investors

Physician

IP Uncertainties

Competition

Resource Limits

Regulatory barriersReimburseme

ntLimited life-cycle

Technical Challenge/FAILURE


Endovascular Peripheral Grafts

ePTFE Vascular Graft

Textile Vascular GraftsCollagen Coated PET

Heart ValvesAnnuloplasty rings

Scaffolds for Tissue engineering

Mesh

for Hernia Repair

Biomaterials in Devices

CoilsBrain Aneurysms

Prosthetic joints

Bone repair - bone plates

Vertebroplasty -Bone cement filling of Compressed vertebrae

Implantable Defibrillator


Materials Selection Guide

Identify: • Predicate Devices • Corporate/Institutional Predicate Devices, Testing, and Regulatory Approvals (510(k)s, PMA’s, and NDA’s) • Corporate/Institutional Guidelines, Procedures and Protocols • FDA Guidelines, CEN Guidelines, and Standards (ASTM, ANSI, ISO) • Corporate/Institutional R&D Reports • Materials, Uses, Properties, ASTM and ISO Standards Develop an Approach for Selection and Testing



MATERIALS SELECTION INDEVICE DESIGN AND TESTING

Functional Requirements

Prioritization of Requirements

Brain StormingMedical Literature and Patents Non-Medical Literature and

Patents

Networking

Design and Processing Approaches

Predicate Devices/Tissue/and Cell Processing and Failure Modes

Corporate/Institutional 510(k)s, PMA’s, NDA’s, Tissue

transplants


Identification of relevant standards/ guidelines and Test Methods

Corporate/Institutional Guidelines, Protocols, and Master FilesRegulatory: FDA, CEN

Standards Organizations: ISO, ANSI, AAMI, ASTM

Biomaterials, Scaffolds, Tissue, and Cell/Tissue Selection and Processing:

RequirementsBiomechanical, Physiochemical, Surface, Durability, Biostability,

Biocompatibility, Immunology (autografts, allografts, xenografts, and cellular engineering), Viability and Thromboresistance

Approach 1 Approach 2 Approach 3 Approach 4

Prototype Component Modeling/Processing and Testing

New Materials and Processes - YesExisting Data - No

Determine Sterilization/Antimicrobial Methods and Testing

Biocompatibility Screening



In Memory of Oscar Ratnoff

Hageman Factor (FXII) and Clotting Cascade

“Failure”of Blood to Clot in a Glass Tube

New UnderstandingFor Biomaterials andBlood ContactingDevices






ISO 10993-1ISO 10993-2ISO 10993-3ISO 10993-4ISO 10993-5ISO 10993-6ISO 10993-7ISO 10993-8ISO 10993-9ISO 10993-10ISO 10993-11ISO 10993-12ISO 10993-13ISO 10993-14ISO 10993-15

ISO 10993-16ISO 10993-17

ISO 10993-18ISO 10993-19ISO 10993-20

Guidance on selection of testsAnimal welfare requirementsTests for genotoxicity, carcinogenicity, and reproductive toxicitySelection of tests for interactions with bloodTests for cytotoxicity: In vitro methodsTests for local effects after implantationEthylene oxide sterilization residualsWithdrawn: Clinical investigation of medical devicesEvaluation of biodegradation of medical devicesTests for irritation and sensitizationTests for systemic toxicitySample preparation and reference materialsIdentification and quantification of degradation products from polymersStatic test to quantify in vitro degradation of ceramicsIdentification and quantification of degradation products from metallic materials used in medical devicesToxicokinetic study design for degradation products and leachablesGlutaraldehyde and formaldehyde residues in industrially sterilized medical devices

Characterization of materials – EXHAUSTIVE EXTRACTIONPhysico-chemical, morphological and topographical characterization of materials Principles and methods for immunotoxicology testing of medical devices

INTERNATIONAL STANDARDS FOR MEDICAL DEVICES


Biocompatibility Issues of Biomaterials Synthetic Plastics, Engineering Plastics, Textiles, and

Hydrogels Extractables Hypersensitivity reactions (e.g. latex materials) 2 part systems and cytotoxic residuals Lipid uptake Hydrolytic stability Biostability Biodegradation by-products Calcification Sterilization residuals Fatigue and wear particulates Protein adsorption: hydrophilic, hydrogel and hydrophobic

M. N. Helmus, D. F. Gibbons, D. Cebon, "Biocompatibility: Meeting a key functional requirement of next-generation medical devices”, Toxicol Pathol 36 (1):70-80, 2008



Guidance for Industry and FDA Staff - Saline, Silicone Gel, and Alternative Breast Implants

Document issued on: November 17, 2006

This document supersedes “Guidance for Saline, Silicone Gel, and Alternative Breast Implants” dated February 11, 2003.

The draft of this document was issued on January 13, 2004.

http://www.fda.gov/cdrh/ode/guidance/1239.html



A design that considers rupture to be

inevitable in trauma would suggest that

a gel-like filler in any mammary prosthesis

must be inherently biocompatible.


Biodegradation

An alteration of the biomaterial or medical device involving loss of integrity or performancein a physiological or simulated environment.


Example Biostability

Polyurethanes

Poyesterurethanes - hydrolytically unstable

Polyetherurethances – ofter grades prone to oxidative enzyme degradation, e.g. 1) acute inflammation, 2) metal ion catalyzed in pacer leads

Polyureaurethanes - generally stables, high fatigue life, not thermally processable, I.e. solution cast

Polycarbonate urethanes - generally stable, low level of hydrolytic degradation possible.




Biodegradables

Rate of biodegradation Surface vs. bulk Particulates Biodegradation by-products Biodeposition Tissue partitioning and excretion Effect of infection (acidic pH) or hematoma (basic pH) on

degradation rates Fatigue and wear particulates


BBiioollooggiiccaallllyy DDeerriivveedd MMaatteerriiaallss:: AArrtteerriieess,, vvaallvveess,, sskkiinn,, dduurraa--mmaatteerr,, bboonnee,, lliiggaammeennttss

Decellularization processes Viability of cells in fresh or Cryopreserved Allografts Cytotoxic preservatives Cross-linking Sterilizability and residuals Biodegradation Calcification Immune responses Biomechanical properties Infectious contamination- bacterial, viral, fungal, and

prion


Bioderived Macromolecules: eg albumin, Chitosans, collagen, gelatin, elastin, fibrin, hyaluronic acid,

phospholipids, silk Purity Extractables Hydrolysis & Biodegradation Hypersensitivity reactions Lipid uptake Sterilization residuals Calcification Inflammatory and immune responses Permeability Water content Degree of cross-linking Effect of cross-linking on inflammation, immune response, and

thrombogenicity Fatigue and wear particulates


Tissue and BiomoleculesTissue and Biomolecules

Collagen Impregnated

Vascular GraftPericardialHeart Valve

Uterine Sling -Repliform ® Tissue Regeneration Matrix, human dermis architecture with cells removed


Typical Bioprosthetic Failure Modes

Pericardial (stenosis)

Porcine (insufficiency & stenosis)

MN Helmus & CM Cunanan, “Mechanical and Bioprosthetic Heart Valves”, in Biomaterials for Artificial Organs, Woodhead Publishing, in Press 4Q 2010


1 7,008,591 Supercritical fluid extraction process for tissue preparation

2 6,964,682 Heart valve holder that resist suture looping

3 6,945,997 Heart valves and suture rings therefor

4 6,837,902 Methods of making bioprosthetic heart valves with strain matched leaflets

5 6,585,766 Cloth-covered stents for tissue heart valves

6 6,413,275 Apparatus for testing bioprosthetic heart valve leaflets

7 6,245,105 Method of testing bioprosthetic heart valve leaflets

8 6,102,944 Methods of tissue heart valve assembly

9 5,961,549 Multi-leaflet bioprosthetic heart valve

10 5,928,281 Tissue heart valves

11 5,880,242 Nonpolymeric epoxy compounds for cross linking biological tissue and

bioprosthetic grafts prepared thereby

In Memory of Ralph Kafesjian

An engineer and innovator inHeart valve design


Failure Analysis Bioprosthetic Valve: Stuck leaflets

Pericardial Heart valve removed shortly after implantation

Leaflets stuck together

Surgeon (outside US) suggested patient had antiphospholipid syndrome

- Coagulation resulted in stuck leaflets


Failure Analysis Bioprosthetic Valve: Stuck leaflets cont.

Operating rooms notes documented the use of fibrin sealant on the sewing ring to mitigate paravalvular leaking

Histopath on leaflets showed an acellular protein layer

PTAH staining was consistent with fibrin

Conclusion: fibrin sealant was responsible for the stuck leaflets


Nature Medicine Published online: 13 January 2008

Perfusion-decellularized matrix: using nature's platform to engineer a bioartificial heart

Harald C Ott1, Thomas S Matthiesen2, Saik-Kia Goh2, Lauren D Black3, Stefan M Kren2, Theoden I Netoff3 & Doris A Taylor2,4

About 3,000 individuals in the United States are awaiting a donor heart; worldwide, 22 million individuals are living with heart failure. A bioartificial heart is a theoretical alternative to transplantation or mechanical left ventricular support. Generating a bioartificial heart requires engineering of cardiac architecture, appropriate cellular constituents and pump function. We decellularized hearts by coronary perfusion with detergents, preserved the underlying extracellular matrix, and produced an acellular, perfusable vascular architecture, competent acellular valves and intact chamber geometry. To mimic cardiac cell composition, we reseeded these constructs with cardiac or endothelial cells. To establish function, we maintained eight constructs for up to 28 d by coronary perfusion in a bioreactor that simulated cardiac physiology. By day 4, we observed macroscopic contractions. By day 8, under physiological load and electrical stimulation, constructs could generate pump function (equivalent to about 2% of adult or 25% of 16-week fetal heart function) in a modified working heart preparation.


Malone, J, et al, 1984

Acelullar vascular matrixWas proposed as a Vascular prosthesis

Early 1980’s


Evaluation for potential immunogenicity

2nd set rejection study in Baboons

acellular canine carotid artery implanted in baboon carotid for 3 weeks

accellular canine carotid implanted in contralateral baboon carotid

Histopath evidence of immune response


Explant analysis paradigm

Implant History—Device, Patient/Animal, Medication (Pre-, Peri- , Postoperative), Patient History, Removal history (revision, autopsy), Gross Photographs insitu and after removal (keeping device moist with saline and limiting time of exposure to air). Blood contacting devices can result in embolic episodes andorgans such as the brain, lungs, and kidneys are particularly important to evaluate for infarcts. Device removal and handling as described below.


Biologic Analyses – An Overlooked component of expant analysis



Material Properties


Passive Coatings: eg Albumin, diamond-like, fluorocarbons, hydrogels, PVD, CVD

Adherence Wear Flaking Uniformity Sterilizability Shelf-life Durability Biostability Extractables Hypersensitivity Lipid uptake Calcification Sterilization residuals Fatigue


Bioactive Coatings (heparin, antimicrobials, cell adhesion peptides, surface charge) and Tissue Adhesives ( Collagen,

cyanoacrylates, fibrin glue, PEG) Degree of antithrombogenicity, cell adhesion & tissue binding Biostability Wear & Durability Uniformity Sterilizability Microbiologic contamination Shelf-life Calcification Immune responses Residuals Tissue Adhesives - Purity - Filtration sterilization - Cure time - Tissue Adhesion


Heparin Release Coating CVC Catheters

US5447724

Medical device polymer

HELMUS MICHAEL N; TOLKOFF M JOSHUA; RALEIGH CAROL L

HARBOR MEDICAL DEVICES INC



2.4x10-4mg/cm2 /hr


Case Study: Processing and heparin release

Particulate heparin in a polyurethane

Release rate decreased (springtime on Atlantic coast)

Reformulated to increase release rate

Product released.

Reports of Hematoma. (Fall season)


Processing and heparin release cont.

In the spring, the humidity increased causing precipitation of the urethane during drying, decreasing release rate.

Reformulated during the summer.

When fall came and dry weather, no precipitation and release rate increased resulting in too high a localized heparin concentration.



Biocompatibilty of Coating

Coating concentration Cytotoxicity – Cell

Culture Rabbit Intramuscular

Implant 0% No Biocompatible

.005% Not tested Biocompatible .1% Yes Biocompatible .3% Not tested Biocompatible .5% Yes Necrosis 1.5 Yes Necrosis

Helmus, Michael N., Scott, Michael J., Enhanced Biocompatibility Coatings for Medical Implants, WO99/38547, Aug. 5, 1999


Intramuscular Rabbit Implants 7 days

Coating concentration > 0.5% DurafloTM

Necrosis and increased host response compared to uncoated controls

Coating concentrations< 0.3 %Biocompatible

Helmus, Michael N., Scott, Michael J., Enhanced Biocompatibility Coatings for Medical Implants, WO99/38547, Aug. 5, 1999

Ex Vivo Canine Shunt 100 ml/min flow

Bioactive Heparin Coatings


Metals and Metallic Alloys Passive layer durability Corrosion - pitting, fretting, stress Corrosion by-products Fracture toughness Fatigue life Stiffness compared to application Porous coatings Hypersensitivity Noble metal protein interactions; Antimicrobial activity, eg. Ag, Cu Wear

Ceramics, Inorganics, and Glasses

Bioactivity and Degree of bone formation Bioresorption rate Biostability Biodegradation by-products Fatigue and wear particulates


Carbons: Pyrolytic, Ultra low temp. isotropic Wear resistance Biostability Low heat of protein adsorption Thromboresistance Fatigue

Composites: Carbon fiber, nanoparticles, radioopacifiers

Surface exposure of compounded particles Extractables Hypersensitivity Residuals Lipid uptake Hydrolytic stability Biostability Biodegradation by-products Calcification Sterilization residuals Fatigue and particulates



Issues:• Stress transfer, sites of highest static and impact stress

• Conformal bearing surface – adhesion & abrasion, particles < 1 micron, osteolysis eg Total Hip• Non-conformal, hi contact stress exceeding strength of UHMWPE , subsurface delamination, pitting, fatigue cracking, particles 2-20 microns, eg Total Knee

• Abrasion of acetabular cup• Effect of gamma/ebeam sterilization on UHMWPE

• Carboxyl formation

• Fatigue life of metal stem• grain size, inclusions, wrought vs cast, surface defects

• Fatigue life of bone cement• formulation - initiator in polymer beads vs monomer• voids, inclusions, poor adhesion to stem poor filling of bone surface


Issues:

• Prosthesis loosening• Noncalcified tissue adjacent to cement leading to micromovement and loosening leading to stem fracture

• mechanical injury to bone during bone cement and stem placement• chemical toxicity of monomer (PMMA)• thermal injury due to exothermic reaction• hypersensitivity to bone cement• surgical technique in removing blood and debris in order to improve penetration into bone


Issues:

• Particles of cement leading to wear of ball and cup

• cement particles and wear particles leading to excessive inflammation and bone resorption – particles < 1 micron

•Diffuse cytoplasmic birefringence

•Citation – T. P. Schmalzried, et al, J Applied Biomaterials, Vol. 5, 185-190 (1994)

• Infection leading to bone resorption


Materials’ Standards for Medical ApplicationsMaterials’ Standards for Medical Applications

ASTM Standards for Materials for ASTM Standards for Materials for Medical DevicesMedical Devices

Example - Example - F 2063 – 00 Standard

Specification for Wrought Nickel-Titanium Shape Memory Alloys for Medical Devices and Surgical Implants


9.2 Non-metallic Inclusions and Porosity:

9.2.1 For all mill products, porosity and nonmetallic inclusions such as Ti4Ni2Ox and TiC particles shall be no larger than 12.5 µm (0.0005 in.). Furthermore, porosity and nonmetallic inclusions shall not constitute more than 1.0 % (area percent) of the structure as viewed at 400X to 500X in any field of view.


SEM to demonstrate

Ti2Ni(Ox)

Inclusion At Origin Of Wire

Fracture

Bend ductility and fatigue endurance limit were negatively impacted by the presence of Ti2Ni(Ox) inclusions


Since the failure had occurred in the cabin area,

engineers did a huge fatigue test of an actual

airplane. They varied the cabin pressure

hydraulically while they flexed the wings. After

three thousand pulsations, a crack appeared near a

cabin window and quickly spread. http://www.uh.edu/engines/

epi1773.htm

http://www.rafmuseum.org.uk/hendon/exhibitions/comet/comet5.cfm

Life Analysis – Comet Jet Experience


B.A.J.704 M. de Mol et al. “Non-destructive assessment of 62 Dutch Bjork-Shiley convexo-concave heart valves”

European Journal of Cardio-thoracic Surgery 11 (1997) 703–709

L. E. Eiselstein and B. James, “Medical Device Failures—Can We Learn from Our Mistakes?” Proceedings from the Materials &

Processes for Medical Devices Conference, M. Helmus, D. Medlin eds., August 25–27, 2004


Replacement Heart Valve Guidance - Draft Document10/14/94 • http://www.fda.gov/cdrh/ode/

3751.html

Replaced by new draft guidance: http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/ GuidanceDocuments/ucm193096.htm


Medical Mess: Implants in Jaw Joints Fail,Leaving Patients In Pain and Disfigured Teflon-Coated Disk Seemed A Boon for TMJD at First But Had Little Testing Bruce Ingersoll and Rose GutfeldStaff Reporters of The Wall Street JournalAugust 31, 1993

-TMJ disorders : arthritis, jaw and facial pain, headaches, earaches, clicking sounds in the jaw, and restricted movement.

-The prosthesis was used to replace an oval disk of cartilage

Image: http://www.ctv.ca/servlet/ArticleNews/story/CTVNews/20070916/Jaw_implants_070916/20070916?hub=Canada


-Prosthesis: 2 layers laminated together - a thin sheath of FEP & a wafer of highly porous Proplast: PTFE, and carbon or aluminum oxide.

-Couldn't withstand the wear and tear of the lower jaw sliding & some cases, it disintegrated within a few months.

-1974 : implants from sheets of laminated Proplast/FEP used to cover the tips of jawbones in TMJD patients.

-1979, sponge-like Proplast was endorsed by the professional society of Oral and Maxillofacial Surgeons as the "living implant" because human tissue could grow into its pores.


-Reported results of 50 jaw implants: "marked pain relief and restoration of jaw movement," according to a press release.

-Never tested in animal jaws before marketing. Company took the position that there was no way to reproduce in a lab animal what happens in the human TMJ.

-No human trials.

-Tests were done on a mechanical simulator that imitates the human jaw.

-Company did not test Proplast and FEP together, as a laminated product


-Simulator testing in an academic lab: sliding back and forth over the prosthesis with 20 pounds of force, wore through the FEP surface into the Proplast backing 100 to 200 times fasted than the wear-rate reported by the company.

-Fractured the thin FEP layer, scattered microscopic particles.

-Predicted "service life" of only one to three years.

-The company did wear-testing: FEP with a metal backing that didn't give way under the 20-pound load. Not a realistic test.


-Only after reports failure began in around 1984 were animal studies done. .. in dogs.

-FEP layer was "completely worn" and particles had triggered bone erosion in the dogs after a few

months. -Company contended the test showed mainly that the dog wasn't a good test animal to use.

-A study at the University of Minnesota dental school in monkeys.

-Proplast/FEP began to fragment after a year, causing "severe degenerative joint changes


Preclinical Efficacy and Safety Testing (Regulatory Guidelines)

Animal implantation for function and durability

Efficacy measure, e.g. repair, functional measurement

- In vivo methods - Radiology, NMR, Echo, Nuclear Medicine, Assays of Blood

- Explant analysis-- Device analysis: physical and surface-- Organ function and Viability-- Tissue histopathology

Clinical Evaluation (Regulatory

Guidelines)


Disruptive Technologies – New Failure Modes

Drug Delivery Therapeutic PolymersBioresorbables Tissue EngineeringStem CellsSmart Materials Imaging, eg Molecular Imaging

GenomicsProteomicsGlycomicsComputationNanoStructuresMEMS


Coronary Artery Disease: Drug Eluting Stents1970’s - 1980’s Bypass Surgery

1980’s Angioplasty

1990’s Stenting (The Problem: Instent Restenosis)

2000’s Drug Eluting Stents

J. Biomed. Mater. Res. 71A:625-634 (2005)

www.heartsurgery-usa.com/On_Pump_Surgery/body_on_pump_surgery.html

www.nlm.nih.gov/medlineplus/ency/presentations/100160_5.htm

www.stormontvail.org/heartcenter/patient_ed/ptca.pdf

Current Controversial Issues: Delayed endothelial Healing and Late Thrombosis


Proposed Solutions

- Biodegradable Coatings

-Rapidly degradable coatings and Abluminal coatings

- New Polymeric Carriers (eg ampiphilic polymers; fluorocarbon copolymers)

- Nonpolymeric carriers, eg porous and nanoporous Ceramics

- New pharmaceuticals for drug delivery coatings

- Bioctive coatings for enhanced healing

-RGD, cell adhesion proteins, GAGs, Heparin Sulfates, Biomimetic growth factors

-Endothelial progenitor and stem cell capture (eg antibodies)


Adverse Publicity of Nanotechnology THE DOWNSIDE OF NANOTECHNOLOGY Boston Globe

November 28, 2005 …Yet the very characteristics that make nanomaterials so promising are also sources of concern about their environmental and health risks. History is littered with technologies that once seemed benign but were discovered years later to have devastating effects on the environment. Examples include the pesticide DDT, marvelously effective at killing insects, but also, it turned out, lethal to birds of prey

like eagles, falcons, and osprey. ...

…But while the ability of some nano particles to pass through a cell could lead to breakthroughs in cancer or Alzheimer's treatment, these same features can pose environmental and health risks. Preliminary studies have shown that some

nanomaterials are able to damage skin, brain, and lung tissue. …

Nanotubes found to be as risky as asbestosMay 21, 2008

The original article is cited on the title only, and the content is ignored. It refers only to multiwalled nanotubes fabricated to the same dimensions as asbestos, not nanotubes that are being evaluated, for example, medical applications.

POLAND CA et al “Carbon nanotubes introduced into the abdominal cavity of mice show asbestos like pathogenicity in a pilot study”, online Nature Nanotechnology, May 20, 2008


Preclinical Safety Assessment for Nanotechnologycont’d)

Our current system is expected to identify possible hazard resulting from drug exposure, due to the extensive pre-clinical evaluation of new drugs.

For nanotechnology drugs:

Are current required studies adequate? YES

Are new testing models needed? MAYBE

http://www.fda.gov/nanotechnology/ChBSA-nanotech-presentation06-04.ppt


Example ofFDA guidancecovering injectable particles thatalso pertain to injectablenanoparticles


The Promise and the Challenge of Nano-enabled technologies for Medical Applications

Enhanced functionality and biocompatibility

Potential new paradigms required for biocompatibility and toxicity evaluations of nano-structures and particles


Embryonic stem cells, Bone marrow & Endothelial precursor cells

Replacing damaged myocardium and vascular tissues

Potential Failure Modes to Consider

Disease pathophysiology and aging leading to dysfunction in endogenous regenerative pathways

- Idiopathic dilated cardiomyopathy

- Atherosclerosis

- Myocardial Infarction

- Tumor angiogenesis

Stem Cell Therapies and Failure?


To Engineer Is Human... Therefore, Admiral Hyman G Rickover, father of the nuclear navy, “Basic Principles for Doing Your Job!”

M. N. Helmus, Details are Important, nature nanotechnology VOL 2 | SEPTEMBER 2007

Ownership: “A person doing a job —any job — must feel that he owns itand that he will remain on that jobindefinitely. …

Responsibility: “Along with Ownershipcomes the need for full acceptanceof full responsibility for the work.Shared responsibility means that noone is responsible.”

Attention to detail: “A tendency amongmanagers, particularly as they moveto higher positions, is to think theyno longer need to be concerned withdetails. If the boss is not concernedabout details, his subordinates also willnot consider them important.”

Priorities: “If you are to manage your job,you must set priorities. … You mustapply self-discipline to ensure your energyis applied where it is most needed.”

Know what is going on: “You mustestablish simple and direct means tofind out what is going on in detail in thearea of your responsibility.”

Hard work: “For this, there is nosubstitute. ....”

Checking up: “An essential element ofcarrying out my work is the need to haveit checked by an independent source.…

Facing the facts: “Another principle formanaging a successful program is to resistthe natural human inclination to hopethings will work out despite evidence ordoubt to the contrary. […] If conditionsrequire it, one must face the facts andbrutally make needed changes despiteconsiderable costs and schedule delays.”